Adverse Menstrual Events Reported After and Before (or Without) COVID-19 Vaccination: A Systematic Review and Meta-Analysis of Comparative Observational Studies.

BACKGROUND: Reports of adverse menstrual events emerged during the COVID-19 vaccination campaign in multiple countries. This raised the question whether these reports were caused by the vaccines. The aim of this systematic review was to evaluate comparative studies on this topic (registered at PROSPERO [CRD42022324973]). METHODS: We included observational studies such as cohort studies and surveys comparing the response to self-reported questionnaires between post- versus pre-vaccination data. PubMed and Cochrane Library searches were conducted on 1 September 2023. The primary outcome was the incidence of any prespecified adverse menstrual event, and the outcome measure was the risk ratio. The meta-analysis was conducted by using the Mantel-Haenszel method and the random effects model. We summarized the results on risk factors as well as key findings of the studies included. RESULTS: We retrieved 161 references from electronic databases and additional sources such as references lists. Of those, we considered 21 comparative observational studies. The meta-analysis of any adverse menstrual adverse event reported in 12 studies resulted in a pooled estimate (risk ratio 1.13; 95% CI, 0.96-1.31) that did not favor any group. The analysis was constrained by considerable clinical and statistical heterogeneity. Risk factors for self-reported menstrual changes included a history of COVID-19 infection, the concern about COVID-19 vaccines, smoking, previous cycle irregularities, depression, and stress, and other issues. CONCLUSIONS: The risk ratio did not favor any group and heterogeneity was prevalent among the studies. Most studies suggested that the reported changes were temporary, minor, and nonserious.

Thin-catheter Surfactant Application for Respiratory Distress Syndrome in Spontaneously Breathing Preterm Infants: A Meta-analysis of Randomized Clinical Trials.

BACKGROUND: Surfactant application by a thin catheter represented by the term less invasive surfactant administration (LISA) for respiratory distress syndrome in spontaneously breathing preterm infants was developed as an alternative to endotracheal intubation. METHODS: We conducted a meta-analysis to assess the effects of LISA when compared to the socalled intubation-surfactant-extubation (INSURE) and the standard endotracheal intubation and mechanical ventilation (MV). The primary outcome was the composite incidence of death or bronchopulmonary dysplasia at a postmenstrual age of 36 weeks. The secondary outcome was the composite incidence of seven other severe adverse events. On 06 October 2021, we searched randomized clinical trials (RCTs) in PubMed, the Cochrane Library, ClinicalTrials.gov, and the ICTRP Registry. RESULTS: We included 18 RCTs. The pooled data on the primary outcome favored LISA when compared to either INSURE (risk ratio 0.67; 95% CI, 0.51 to 0.88) or MV (risk ratio 0.78; 95% CI, 0.61 to 0.99). The pooled data on the second outcome also favored LISA when compared to INSURE (risk ratio 0.75; 95% CI, 0.60 to 0.94) and MV (risk ratio 0.73; 95% CI, 0.55 to 0.96). CONCLUSION: The findings showed that surfactant application by non-intubation respiratory support and the use of a thin catheter may decrease the composite risk of death or bronchopulmonary dysplasia. The included data support the view that LISA should be considered the preferred treatment option in eligible infants.

Extracorporeal photopheresis for systemic sclerosis: A meta-analysis of randomized clinical trials.

Systemic sclerosis (scleroderma) (SSc) is a rare autoimmune disorder characterized by excessive production of collagen. Extracorporeal photopheresis (photochemotherapy, phototherapy) (ECP) involves repeated exposure of peripheral blood lymphocytes to ultraviolet A (UVA) radiation. The rationale for treating patients with SSc by ECP lies in its presumed immunomodulatory effects, though, rigorous data on the specific effects of ECP are limited, particularly in patients with SSc. The objective was to evaluate the effects of extracorporeal photopheresis as a treatment modality for patients with SSc. We searched the databases CENTRAL and MEDLINE on 13 March 2022 and included randomized clinical trials (RCTs) on patients diagnosed with SSc and treated with ECP. Primary outcome was the change of skin scores. We applied independent extraction and judgment by multiple observers. We conducted a meta-analysis applying the inverse variance method and the random effects model; the main outcome measure was standard mean difference of skin scores. We identified three relevant RCTs including 162 randomized (132 analyzed) people who received ECP in a simple parallel design. Pooled data of the three studies were indifferent. We estimated a standard mean difference from baseline of -0.11 (95% confidence interval -0.45 to 0.23), p = 0.54, I2  = 0%. We did not identify serious treatment-related adverse events. The evidence base for extracorporeal photopheresis on skin scores in patients with systemic sclerosis was not high enough to support a superior effect when compared to no treatment, sham photopheresis, or D-penicillamine.

Indoor balneophototherapy for chronic plaque psoriasis: Abridged Cochrane Review.

Artificial exposure to ultraviolet B light (UVB) while soaking in an indoor salt bath, also called balneophototherapy, could simulate the natural exposure to the sun while bathing in the Dead Sea. We aimed to assess the effects of this intervention on patients with chronic plaque psoriasis. We searched CENTRAL, MEDLINE, Embase, and LILACS up to June 2019. We included randomized controlled trials (RCTs). The primary efficacy outcome was psoriasis area and severity index (PASI)-75 to detect people with a 75% or more reduction in the PASI score from baseline. The primary adverse outcome was treatment-related adverse events requiring withdrawal. We included eight RCTs (2105 participants; 1976 analyzed). With respect to PASI-75, two studies found that salt bath + UVB may improve psoriasis when compared to UVB alone (risk ratio 1.71, 95% confidence interval 1.24 to 2.35; 278 participants). With respect to treatment-related adverse events requiring withdrawal, two other studies found little to no difference when compared to UVB alone (risk ratio 0.96, 95% confidence interval 0.35 to 2.64; 404 participants). Salt bath + UVB could improve psoriasis when compared to UVB alone, though, results are based on a limited number of studies and provide low-certainty evidence.

Evidence-based topical treatments (azelaic acid, salicylic acid, nicotinamide, sulfur, zinc, and fruit acid) for acne: an abridged version of a Cochrane systematic review.

OBJECTIVE: The effects of topical azelaic acid, salicylic acid, nicotinamide, sulfur, zinc, and fruit acid (alpha-hydroxy acid) for acne are unclear. We aimed to assess the effects of these topical treatments by collecting randomized controlled trials. METHODS: We searched The Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS up to May 2019. We also searched five trials registers. Two review authors independently extracted data and assessed risk of bias. Meta analyses were performed by using Review Manager 5 software. RESULTS: We included a total of 49 trials involving 3880 participants. In terms of treatment response (measured using participants' global self-assessment of acne improvement, PGA), azelaic acid was probably less effective than benzoyl peroxide (RR = 0.82, 95% CI 0.72-0.95). However, there was probably little or no difference in PGA when comparing azelaic acid to tretinoin (RR = 0.94, 95% CI 0.78-1.14). There may be little or no difference when comparing salicylic acid to tretinoin (RR = 1.00, 95% CI 0.92-1.09). There were no studies measured PGA when evaluating nicotinamide. With respect to alpha-hydroxy acid, there may be no difference in PGA when comparing glycolic acid to salicylic-mandelic acid (RR = 1.06, 95% CI 0.88-1.26). We were uncertain about the effects of sulfur and zinc. Adverse events associated with these topical treatments were always mild and transient. CONCLUSIONS: Moderate-quality evidence was available for azelaic acid and low- to very-low-quality evidence for other topical treatments. Risk of bias and imprecision limit our confidence in the evidence.

Indoor salt water baths followed by artificial ultraviolet B light for chronic plaque psoriasis.

BACKGROUND: Chronic plaque psoriasis is an immune-mediated, chronic, inflammatory skin disease, which can impair quality of life and social interaction. Disease severity can be classified by the psoriasis area and severity index (PASI) score ranging from 0 to 72 points. Indoor artificial salt bath with or without artificial ultraviolet B (UVB) light is used to treat psoriasis, simulating sea bathing and sunlight exposure; however, the evidence base needs clear evaluation. OBJECTIVES: To assess the effects of indoor (artificial) salt water baths followed by exposure to artificial UVB for treating chronic plaque psoriasis in adults. SEARCH METHODS: We searched the following databases up to June 2019: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trial registers, and checked the reference lists of included studies, recent reviews, and relevant papers for further references to relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) of salt bath indoors followed by exposure to artificial UVB in adults who have been diagnosed with chronic plaque type psoriasis. We included studies reporting between-participant data and within-participant data. We evaluated two different comparisons: 1) salt bath + UVB versus other treatment without UVB; eligible comparators were exposure to psoralen bath, psoralen bath + artificial ultraviolet A UVA) light, topical treatment, systemic treatment, or placebo, and 2) salt bath + UVB versus other treatment + UVB or UVB only; eligible comparators were exposure to bath containing other compositions or concentrations + UVB or UVB only. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of the evidence. The primary efficacy outcome was PASI-75, to detect people with a 75% or more reduction in PASI score from baseline. The primary adverse outcome was treatment-related adverse events requiring withdrawal. For the dichotomous variables PASI-75 and treatment-related adverse events requiring withdrawal, we estimated the proportion of events among the assessed participants. The secondary outcomes were health-related quality of life using the Dermatology Life Quality Index, (DLQI) pruritus severity measured using a visual analogue scale, time to relapse, and secondary malignancies. MAIN RESULTS: We included eight RCTs: six reported between-participant data (2035 participants; 1908 analysed), and two reported within-participant data (70 participants, 68 analysed; 140 limbs; 136 analysed). One study reported data for the comparison salt bath with UVB versus other treatment without UVB; and eight studies reported data for salt bath with UVB versus other treatment with UVB or UVB only. Of these eight studies, only five reported any of our pre-specified outcomes and assessed the comparison of salt bath with UVB versus UVB only. The one included trial that assessed salt bath plus UVB versus other treatment without UVB (psoralen bath + UVA) did not report any of our primary outcomes. The mean age of the participants ranged from 41 to 50 years of age in 75% of the studies. None of the included studies reported on the predefined secondary outcomes of this review. We judged seven of the eight studies as at high risk of bias in at least one domain, most commonly performance bias. Total trial duration ranged between at least two months and up to 13 months. In five studies, the median participant PASI score at baseline ranged from 15 to 18 and was balanced between treatment arms. Three studies did not report PASI score. Most studies were conducted in Germany; all were set in Europe. Half of the studies were multi-centred (set in spa centres or outpatient clinics); half were set in a single centre in either an unspecified settings, a psoriasis daycare centre, or a spa centre. Commercial spa or salt companies sponsored three of eight studies, health insurance companies funded another, the association of dermatologists funded another, and three did not report on funding. When comparing salt bath plus UVB versus UVB only, two between-participant studies found that salt bath plus UVB may improve psoriasis when measured using PASI 75 (achieving a 75% or more reduction in PASI score from baseline) (risk ratio (RR) 1.71, 95% confidence interval (CI) 1.24 to 2.35; 278 participants; low-certainty evidence). Assessment was conducted at the end of treatment, which was equivalent to six to eight weeks after start of treatment. The two trials which contributed data for the primary efficacy outcome were conducted by the same group, and did not blind outcome assessors. The German Spas Association funded one of the trials and the funding source was not stated for the other trial. Two other between-participant studies found salt bath plus UVB may make little to no difference to outcome treatment-related adverse events requiring withdrawal compared with UVB only (RR 0.96, 95% CI 0.35 to 2.64; 404 participants; low-certainty evidence). One of the studies reported adverse events, but did not specify the type of events; the other study reported skin irritation. One within-participant study found similar results, with one participant reporting severe itch immediately after Dead Sea salt soak in the salt bath and UVB group and two instances of inadequate response to phototherapy and conversion to psoralen bath + UVA reported in the UVB only group (low-certainty evidence). AUTHORS' CONCLUSIONS: Salt bath with artificial ultraviolet B (UVB) light may improve psoriasis in people with chronic plaque psoriasis compared with UVB light treatment alone, and there may be no difference in the occurrence of treatment-related adverse events requiring withdrawal. Both results are based on data from a limited number of studies, which provided low-certainty evidence, so we cannot draw any clear conclusions. The reporting of our pre-specified outcomes was either non-existent or limited, with a maximum of two studies reporting a given outcome. The same group conducted the two trials which contributed data for the primary efficacy outcome, and the German Spas Association funded one of these trials. We recommend further RCTs that assess PASI-75, with detailed reporting of the outcome and time point, as well as treatment-related adverse events. Risk of bias was an issue; future studies should ensure blinding of outcome assessors and full reporting.

Topical azelaic acid, salicylic acid, nicotinamide, sulphur, zinc and fruit acid (alpha-hydroxy acid) for acne.

BACKGROUND: Acne is an inflammatory disorder with a high global burden. It is common in adolescents and primarily affects sebaceous gland-rich areas. The clinical benefit of the topical acne treatments azelaic acid, salicylic acid, nicotinamide, sulphur, zinc, and alpha-hydroxy acid is unclear. OBJECTIVES: To assess the effects of topical treatments (azelaic acid, salicylic acid, nicotinamide, zinc, alpha-hydroxy acid, and sulphur) for acne. SEARCH METHODS: We searched the following databases up to May 2019: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers. SELECTION CRITERIA: Clinical randomised controlled trials of the six topical treatments compared with other topical treatments, placebo, or no treatment in people with acne. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Key outcomes included participants' global self-assessment of acne improvement (PGA), withdrawal for any reason, minor adverse events (assessed as total number of participants who experienced at least one minor adverse event), and quality of life. MAIN RESULTS: We included 49 trials (3880 reported participants) set in clinics, hospitals, research centres, and university settings in Europe, Asia, and the USA. The vast majority of participants had mild to moderate acne, were aged between 12 to 30 years (range: 10 to 45 years), and were female. Treatment lasted over eight weeks in 59% of the studies. Study duration ranged from three months to three years. We assessed 26 studies as being at high risk of bias in at least one domain, but most domains were at low or unclear risk of bias. We grouped outcome assessment into short-term (less than or equal to 4 weeks), medium-term (from 5 to 8 weeks), and long-term treatment (more than 8 weeks). The following results were measured at the end of treatment, which was mainly long-term for the PGA outcome and mixed length (medium-term mainly) for minor adverse events. Azelaic acid In terms of treatment response (PGA), azelaic acid is probably less effective than benzoyl peroxide (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.72 to 0.95; 1 study, 351 participants), but there is probably little or no difference when comparing azelaic acid to tretinoin (RR 0.94, 95% CI 0.78 to 1.14; 1 study, 289 participants) (both moderate-quality evidence). There may be little or no difference in PGA when comparing azelaic acid to clindamycin (RR 1.13, 95% CI 0.92 to 1.38; 1 study, 229 participants; low-quality evidence), but we are uncertain whether there is a difference between azelaic acid and adapalene (1 study, 55 participants; very low-quality evidence). Low-quality evidence indicates there may be no differences in rates of withdrawal for any reason when comparing azelaic acid with benzoyl peroxide (RR 0.88, 95% CI 0.60 to 1.29; 1 study, 351 participants), clindamycin (RR 1.30, 95% CI 0.48 to 3.56; 2 studies, 329 participants), or tretinoin (RR 0.66, 95% CI 0.29 to 1.47; 2 studies, 309 participants), but we are uncertain whether there is a difference between azelaic acid and adapalene (1 study, 55 participants; very low-quality evidence). In terms of total minor adverse events, we are uncertain if there is a difference between azelaic acid compared to adapalene (1 study; 55 participants) or benzoyl peroxide (1 study, 30 participants) (both very low-quality evidence). There may be no difference when comparing azelaic acid to clindamycin (RR 1.50, 95% CI 0.67 to 3.35; 1 study, 100 participants; low-quality evidence). Total minor adverse events were not reported in the comparison of azelaic acid versus tretinoin, but individual application site reactions were reported, such as scaling. Salicylic acid For PGA, there may be little or no difference between salicylic acid and tretinoin (RR 1.00, 95% CI 0.92 to 1.09; 1 study, 46 participants; low-quality evidence); we are not certain whether there is a difference between salicylic acid and pyruvic acid (1 study, 86 participants; very low-quality evidence); and PGA was not measured in the comparison of salicylic acid versus benzoyl peroxide. There may be no difference between groups in withdrawals when comparing salicylic acid and pyruvic acid (RR 0.89, 95% CI 0.53 to 1.50; 1 study, 86 participants); when salicylic acid was compared to tretinoin, neither group had withdrawals (both based on low-quality evidence (2 studies, 74 participants)). We are uncertain whether there is a difference in withdrawals between salicylic acid and benzoyl peroxide (1 study, 41 participants; very low-quality evidence). For total minor adverse events, we are uncertain if there is any difference between salicylic acid and benzoyl peroxide (1 study, 41 participants) or tretinoin (2 studies, 74 participants) (both very low-quality evidence). This outcome was not reported for salicylic acid versus pyruvic acid, but individual application site reactions were reported, such as scaling and redness. Nicotinamide Four studies evaluated nicotinamide against clindamycin or erythromycin, but none measured PGA. Low-quality evidence showed there may be no difference in withdrawals between nicotinamide and clindamycin (RR 1.12, 95% CI 0.49 to 2.60; 3 studies, 216 participants) or erythromycin (RR 1.40, 95% CI 0.46 to 4.22; 1 study, 158 participants), or in total minor adverse events between nicotinamide and clindamycin (RR 1.20, 95% CI 0.73 to 1.99; 3 studies, 216 participants; low-quality evidence). Total minor adverse events were not reported in the nicotinamide versus erythromycin comparison. Alpha-hydroxy (fruit) acid There may be no difference in PGA when comparing glycolic acid peel to salicylic-mandelic acid peel (RR 1.06, 95% CI 0.88 to 1.26; 1 study, 40 participants; low-quality evidence), and we are uncertain if there is a difference in total minor adverse events due to very low-quality evidence (1 study, 44 participants). Neither group had withdrawals (2 studies, 84 participants; low-quality evidence). AUTHORS' CONCLUSIONS: Compared to benzoyl peroxide, azelaic acid probably leads to a worse treatment response, measured using PGA. When compared to tretinoin, azelaic acid probably makes little or no difference to treatment response. For other comparisons and outcomes the quality of evidence was low or very low. Risk of bias and imprecision limit our confidence in the evidence. We encourage the comparison of more methodologically robust head-to-head trials against commonly used active drugs.

Quality issues identified in systematic reviews on platelet-rich plasma therapy for pattern hair loss-A method study.

BACKGROUND: Systematic reviews of healthcare interventions aim to evaluate the quality of clinical studies, but they might have quality issues in their own right. OBJECTIVE: We aimed to evaluate methodological inconsistencies in systematic reviews. METHODS: We searched the database MEDLINE and included systematic reviews and/or meta-analyses on platelet-rich plasma therapy for pattern hair loss. RESULTS: We identified 15 relevant systematic reviews and/or meta-analyses, and we identified various overt methodological inconsistencies in five of those systematic reviews. These inconsistencies concerned including duplicate data, mixing data from various study designs, misclassifying study designs and treatment comparisons, misinterpreting heterogeneity, and mistaking reporting standards. CONCLUSION: The identification of various inconsistencies in previous systematic reviews on platelet-rich plasma therapy for pattern hair loss should prompt future authors to consult the Cochrane Handbook and to implement the PRISMA statement.

Early laser intervention to reduce scar formation in wound healing by primary intention: A systematic review.

BACKGROUND: Hypertrophic scars frequently follow primary closure of surgical wounds. Laser application at or shortly after suture may be associated with a reduction in scar formation, although the respective study results vary. AIM: The objective was to evaluate the efficacy of early laser applied within the first six months after surgery to reduce scar formation compared to no treatment. METHODS: We searched the databases MEDLINE and CENTRAL on 14 January 2019 and included randomized controlled trials (RCTs). Primary outcome was the Vancouver Scar Scale (VSS). Measure of treatment effect was the mean difference from baseline. RESULTS: Seventeen relevant RCTs randomized 430 scars (413 assessed) and compared laser versus no treatment. Fourteen studies applied a split-scar and three applied a simple parallel design. Three studies with a split-scar design favored the laser group on VSS, and one study had indifferent findings. Considerable heterogeneity I2 = 86% did not justify a meta-analysis. The remaining 13 studies did not report appropriate data. CONCLUSION: On the basis of the currently available evidence, we are uncertain whether early laser can reduce scar formation, and more high-quality research is needed for a definitive conclusion.

Autologous platelet-rich plasma therapy for pattern hair loss: A systematic review.

BACKGROUND: Androgenetic alopecia (male pattern and female pattern hair loss) is characterized by thinning of the scalp hair. Intradermal injection of autologous platelet-rich plasma (PRP) might have an effect on hair regrowth. AIMS: The aim was to evaluate efficacy and safety of platelet-rich plasma compared to placebo or no treatment in people with pattern hair loss. PATIENTS/METHODS: We searched the databases CENTRAL and MEDLINE on December 24, 2018 and included randomized controlled trials (RCTs). Primary outcomes were mean change of hair density from baseline and serious treatment-related adverse events. Secondary outcome was mean change of hair thickness from baseline. Time point of outcome assessment was 6 months after start of treatment. RESULTS: We identified 13 relevant randomized controlled trials with 356 randomized (343 analyzed) people or half-head areas who received PRP in a simple parallel or half-head design. The pooled data of seven studies (171 analyzed people or half-head areas) were favorable in the PRP group on hair density. We estimated a mean difference from baseline of 30.35 associated with a wide 95% confidence interval (1.77-58.93), a considerable heterogeneity (I2  = 100%), and unclear risk of bias in most of the studies. Regarding hair thickness, data were also favorable in the PRP group, but these data were limited to a single study. We did not identify serious treatment-related adverse events. CONCLUSION: The results of seven RCTs indicated that autologous platelet-rich plasma was associated with an increase of hair density when compared to placebo.

Serious Game-based Intervention for Children with Developmental Disabilities.

BACKGROUND: Children with developmental disabilities may need support with motor skills such as balance improvement, cognitive skills such as vocabulary learning, or social skills such as adequate interpretation of emotional expressions. Digital interactive games could support the standard treatments. We aimed to review clinical studies which investigated the application of serious games in children with developmental disabilities. METHODS: We searched MEDLINE and Scopus on 05 May 2019 limited to the English language. We included people between two and 24 years of age who were affected by neurodevelopmental disorders and who received digital serious game-based medical interventions such as any computer- based or video-based games. We considered any study design reporting primary data. We used title, abstract, and full-text of journal articles to build diagnostic groups, and we described some selected specific game applications. RESULTS: The majority of the 145 relevant studies reported on autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), developmental coordination disorder (DCD), and disabilities affecting intellectual abilities (DAIA). 30 of the 145 studies reported a randomized design. We detailed six specific applications aimed at improving abilities in children with ASD, ADHD, cerebral palsy, and Down syndrome. We visualized the diagnostic groups by bibliographic mapping, and limited the text to the title and abstract of journal articles. CONCLUSION: We identified promising results regarding anxiety reduction, stress regulation, emotion recognition, and rehabilitation. Currently, there appears to be a lack of clinical evidence that children with neurodevelopmental disorders can benefit from the application of serious games.

Immunotherapy for metastatic renal cell carcinoma: A systematic review.

BACKGROUND: Various approaches have been developed for the treatment of metastatic renal cell carcinoma (MRCC). The objective was to assess the efficacy of immunotherapeutic approaches. METHODS: We included participants diagnosed with all types of histologically confirmed MRCC, the test intervention was immunotherapy alone or combined with other immunotherapy or targeted therapies, and the study design was restricted to randomized controlled trials (RCTs). Primary outcomes were overall survival, adverse events, and health-related quality of life. We conducted the last search in March 31, 2018. RESULTS: We included nine RCTs, and we established seven different treatment comparisons according to the type of data. Two RCTs favored nivolumab as monotherapy or combined with ipilimumab on account of all primary outcomes. The efficacy data of all other comparisons were either indifferent or favored the control group. CONCLUSION: The immune checkpoint inhibitors nivolumab as monotherapy or combined with ipilimumab appears to be the only new immunotherapy that may improve overall survival in participants with metastatic renal cell carcinoma. Interferon-α alone is unfavorable to targeted therapies with respect to overall survival and adverse events.

Anti-GD2 antibody-containing immunotherapy postconsolidation therapy for people with high-risk neuroblastoma treated with autologous haematopoietic stem cell transplantation.

BACKGROUND: Neuroblastoma is a rare malignant disease that primarily affects children. The tumours mainly develop in the adrenal medullary tissue, and an abdominal mass is the most common presentation. High-risk disease is characterised by metastasis and other primary tumour characteristics resulting in increased risk for an adverse outcome. The GD2 carbohydrate antigen is expressed on the cell surface of neuroblastoma tumour cells and is thus a promising target for anti-GD2 antibody-containing immunotherapy. OBJECTIVES: To assess the efficacy of anti-GD2 antibody-containing postconsolidation immunotherapy after high-dose chemotherapy (HDCT) and autologous haematopoietic stem cell transplantation (HSCT) compared to standard therapy after HDCT and autologous HSCT in people with high-risk neuroblastoma. Our primary outcomes were overall survival and treatment-related mortality. Our secondary outcomes were progression-free survival, event-free survival, early toxicity, late non-haematological toxicity, and health-related quality of life. SEARCH METHODS: We searched the electronic databases CENTRAL (2018, Issue 9), MEDLINE (PubMed), and Embase (Ovid) on 20 September 2018. We searched trial registries and conference proceedings on 28 October 2018. Further searches included reference lists of recent reviews and relevant articles as well as contacting experts in the field. There were no limits on publication year or language. SELECTION CRITERIA: Randomised controlled trials evaluating anti-GD2 antibody-containing immunotherapy after HDCT and autologous HSCT in people with high-risk neuroblastoma. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, abstracted data on study and participant characteristics, and assessed risk of bias and GRADE. Any differences were resolved by discussion, with third-party arbitration unnecessary. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We used the five GRADE considerations, that is study limitations, consistency of effect, imprecision, indirectness, and publication bias, to judge the quality of the evidence. MAIN RESULTS: We identified one randomised controlled trial that included 226 people with high-risk neuroblastoma who were pre-treated with autologous HSCT. The study randomised 113 participants to receive immunotherapy including isotretinoin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and ch14.18, a type of anti-GD2 antibody also known as dinutuximab. The study randomised another 113 participants to receive standard therapy including isotretinoin.The results on overall survival favoured the dinutuximab-containing immunotherapy group (hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31 to 0.80; P = 0.004). The results on event-free survival also favoured the dinutuximab-containing immunotherapy group (HR 0.61, 95% CI 0.41 to 0.92; P = 0.020). Randomised data on adverse events were not reported separately. The study did not report progression-free survival, late non-haematological toxicity, and health-related quality of life as separate endpoints. We graded the quality of the evidence as moderate. AUTHORS' CONCLUSIONS: The evidence base favours dinutuximab-containing immunotherapy compared to standard therapy concerning overall survival and event-free survival in people with high-risk neuroblastoma pre-treated with autologous HSCT. Randomised data on adverse events are lacking, therefore more research is needed before definitive conclusions can be made regarding this outcome.

Varying results of early benefit assessment of newly approved pharmaceutical drugs in Germany from 2011 to 2017: A study based on federal joint committee data.

BACKGROUND: Since January 2011, the Federal Joint Committee (FJC) conducts early benefit assessments (EBA) of newly approved pharmaceutical drugs compared to appropriate standard therapies. The FJC commissions the Institute for Quality and Efficiency in Healthcare (IQEH) to prepare preliminary reports. We aimed to evaluate the extent, impact, and reason for different judgments on added benefit of both institutions. METHODS: We searched EBA data on the FJC website and included completed procedures from 2011 to 2017. We conducted a quantitative analysis of the difference between FJC and IQEH on divergent judgments, a quantitative analysis of the impact of EBA on market withdrawal, and a qualitative analysis to identify potential factors contributing to divergent judgments. RESULTS: FJC rated an added benefit in 30% (139 of 457) and IQEH in 22% (101 of 457) matching research questions (P = 0.004). In the aftermath of EBA, 28 pharmaceutical drugs were withdrawn from the German market. We identified three potential factors that might have contributed to the divergent judgments. IQEH used a unique threshold concept to define the rating, FJC conducted additional public hearings, and FJC showed more flexibility with adherence to stringent criteria and interpretation of results. CONCLUSIONS: FJC and IQEH differed significantly in their early benefit assessment. In response to negative EBA decisions, pharmaceutical companies withdrew a considerable number of medicines from the German market. The present work uncovers the subjectivity and possible variance inherent in benefit assessment, as the two institutions observe the same rules of procedure.

Negative pressure wound therapy: A systematic review of randomized controlled trials from 2000 to 2017.

BACKGROUND: Negative pressure wound therapy (NPWT) proposes to provide better wound healing than standard wound management. Evidence quality of randomized controlled trials (RCTs) varies. METHODS: We included participants with any kind of wounds and commercial as well as the homemade NPWT system. Comparators were any other wound dressing including variant NPWTs. We included RCTs randomizing patients or wounds in parallel or crossover designs. We searched PubMed and Cochrane Library on January 03, 2018. We assessed the risk of bias according to Cochrane and appropriateness of clinical endpoints according to the Food and Drug Administration (FDA). RESULTS: We included 93 RCTs originating in 30 countries, 70 studies on open wounds and 23 studies on closed wounds. With respect to random sequence generation, we judged an unclear or high risk of bias in 50% (47 of 93) studies. With respect to allocation concealment, we judged an unclear or high risk of bias in 90% (84 of 93). We identified 41% (38 of 93) studies that based their conclusion on not appropriate endpoints. CONCLUSIONS: High risk of bias concerning random sequence generation and allocation concealment limited the credibility of the majority of 93 included RCTs on NPWT. A low risk of bias can and should be achieved with both items, and we recommend to align future RCTs to Cochrane. Many primary clinical endpoints were deemed not valid for making inferences on the efficacy of NPWT. We recommend using patient-centered endpoints as requested by the FDA and suggested in the present systematic review.

Negative pressure wound therapy for treating foot wounds in people with diabetes mellitus.

BACKGROUND: Foot wounds in people with diabetes mellitus (DM) are a common and serious global health issue. People with DM are prone to developing foot ulcers and, if these do not heal, they may also undergo foot amputation surgery resulting in postoperative wounds. Negative pressure wound therapy (NPWT) is a technology that is currently used widely in wound care. NPWT involves the application of a wound dressing attached to a vacuum suction machine. A carefully controlled negative pressure (or vacuum) sucks wound and tissue fluid away from the treated area into a canister. A clear and current overview of current evidence is required to facilitate decision-making regarding its use. OBJECTIVES: To assess the effects of negative pressure wound therapy compared with standard care or other therapies in the treatment of foot wounds in people with DM in any care setting. SEARCH METHODS: In January 2018, for this first update of this review, we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies, reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. We identified six additional studies for inclusion in the review. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) that evaluated the effects of any brand of NPWT in the treatment of foot wounds in people with DM, irrespective of date or language of publication. Particular effort was made to identify unpublished studies. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. Initial disagreements were resolved by discussion, or by including a third review author when necessary. We presented and analysed data separately for foot ulcers and postoperative wounds. MAIN RESULTS: Eleven RCTs (972 participants) met the inclusion criteria. Study sample sizes ranged from 15 to 341 participants. One study had three arms, which were all included in the review. The remaining 10 studies had two arms. Two studies focused on postamputation wounds and all other studies included foot ulcers in people with DM. Ten studies compared NPWT with dressings; and one study compared NPWT delivered at 75 mmHg with NPWT delivered at 125 mmHg. Our primary outcome measures were the number of wounds healed and time to wound healing.NPWT compared with dressings for postoperative woundsTwo studies (292 participants) compared NPWT with moist wound dressings in postoperative wounds (postamputation wounds). Only one study specified a follow-up time, which was 16 weeks. This study (162 participants) reported an increased number of healed wounds in the NPWT group compared with the dressings group (risk ratio (RR) 1.44, 95% confidence interval (CI) 1.03 to 2.01; low-certainty evidence, downgraded for risk of bias and imprecision). This study also reported that median time to healing was 21 days shorter with NPWT compared with moist dressings (hazard ratio (HR) calculated by review authors 1.91, 95% CI 1.21 to 2.99; low-certainty evidence, downgraded for risk of bias and imprecision). Data from the two studies suggest that it is uncertain whether there is a difference between groups in amputation risk (RR 0.38, 95% CI 0.14 to 1.02; 292 participants; very low-certainty evidence, downgraded once for risk of bias and twice for imprecision).NPWT compared with dressings for foot ulcersThere were eight studies (640 participants) in this analysis and follow-up times varied between studies. Six studies (513 participants) reported the proportion of wounds healed and data could be pooled for five studies. Pooled data (486 participants) suggest that NPWT may increase the number of healed wounds compared with dressings (RR 1.40, 95% CI 1.14 to 1.72; I² = 0%; low-certainty evidence, downgraded once for risk of bias and once for imprecision). Three studies assessed time to healing, but only one study reported usable data. This study reported that NPWT reduced the time to healing compared with dressings (hazard ratio (HR) calculated by review authors 1.82, 95% CI 1.27 to 2.60; 341 participants; low-certainty evidence, downgraded once for risk of bias and once for imprecision).Data from three studies (441 participants) suggest that people allocated to NPWT may be at reduced risk of amputation compared with people allocated to dressings (RR 0.33, 95% CI 0.15 to 0.70; I² = 0%; low-certainty evidence; downgraded once for risk of bias and once for imprecision).Low-pressure compared with high-pressure NPWT for foot ulcersOne study (40 participants) compared NPWT 75 mmHg and NPWT 125 mmHg. Follow-up time was four weeks. There were no data on primary outcomes. There was no clear difference in the number of wounds closed or covered with surgery between groups (RR 0.83, 95% CI 0.47 to 1.47; very low-certainty evidence, downgraded once for risk of bias and twice for serious imprecision) and adverse events (RR 1.50, 95% CI 0.28 to 8.04; very low-certainty evidence, downgraded once for risk of bias and twice for serious imprecision). AUTHORS' CONCLUSIONS: There is low-certainty evidence to suggest that NPWT, when compared with wound dressings, may increase the proportion of wounds healed and reduce the time to healing for postoperative foot wounds and ulcers of the foot in people with DM. For the comparisons of different pressures of NPWT for treating foot ulcers in people with DM, it is uncertain whether there is a difference in the number of wounds closed or covered with surgery, and adverse events. None of the included studies provided evidence on time to closure or coverage surgery, health-related quality of life or cost-effectiveness. The limitations in current RCT evidence suggest that further trials are required to reduce uncertainty around decision-making regarding the use of NPWT to treat foot wounds in people with DM.

Issues possibly associated with misinterpreting survival data: A method study.

OBJECTIVE: Proper interpretation of survival data of clinical cancer studies may be difficult and pitfalls related to the nature of Kaplan-Meier analyses might end up in mistaken inferences. The purpose of the present work is to raise awareness of those pitfalls and to prevent errors in future studies. STUDY DESIGN AND SETTING: While evaluating a randomized controlled trial, we came across some issues possibly associated with misinterpreting survival data. We thoroughly reviewed the reporting of survival analyses, statistical approaches, baseline characteristics, and choice of primary end point. The reported data were derived from people with high-risk neuroblastoma. Thus, the trial focused on survival. We reenacted survival functions by deducing the data of various treatment groups from pictured survival functions to estimate the concerning hazard ratios. RESULTS: Opposed to the reporting of the trial, we did not identify a significant difference between treatment groups with respect to overall survival. We were not able to appreciate an effective crossing of survival curves. With respect to event-free survival, we focused on comparable treatment groups and we did not identify a significant difference between treatment groups, thereby again opposing the reporting of the trial. CONCLUSIONS: The present work exemplifies statistical issues that were apparently difficult to detect and that are possibly associated with misinterpreting survival functions. These issues include assumed crossing of survival curves, statistical approach changed in follow-up, different pretreatment between groups, and event-free survival used as primary outcome. Careful handling might prevent similar potential misinterpretation in future studies.

Point-of-care treatment of focal cartilage defects with selected chondrogenic mesenchymal stromal cells-An in vitro proof-of-concept study.

Due to the poor self-healing capacities of cartilage, innovative approaches are a major clinical need. The use of in vitro expanded mesenchymal stromal cells (MSCs) in a 2-stage approach is accompanied by cost-, time-, and personnel-intensive good manufacturing practice production. A 1-stage intraoperative procedure could overcome these drawbacks. The aim was to prove the feasibility of a point-of-care concept for the treatment of cartilage lesions using defined MSC subpopulations in a collagen hydrogel without prior MSC monolayer expansion. We tested 4 single marker candidates (MSCA-1, W4A5, CD146, CD271) for their effectiveness of separating colony-forming units of ovine MSCs via magnetic cell separation. The most promising surface marker with regard to the highest enrichment of colony-forming cells was subsequently used to isolate a MSC subpopulation for the direct generation of a cartilage graft composed of a collagen type I hydrogel without the propagation of MSCs in monolayer. We observed that separation with CD271 sustained the highest enrichment of colony-forming units. We then demonstrated the feasibility of generating a cartilage graft with an unsorted bone marrow mononuclear cell fraction and with a characterized CD271 positive MSC subpopulation without the need for a prior cell expansion. A reduced volume of 6.25% of the CD271 positive MSCs was needed to achieve the same results regarding chondrogenesis compared with the unseparated bone marrow mononuclear cell fraction, drastically reducing the number of nonrelevant cells. This study provides a proof-of-concept and reflects the potential of an intraoperative procedure for direct seeding of cartilage grafts with selected CD271 positive cells from bone marrow.

Blood pressure and cholesterol level checks as dynamic interrelated screening examinations.

This study analysed the determinants of screening uptake for blood pressure and cholesterol level checks. Furthermore, it investigated the presence of possible spillover effects from one type of cardiovascular screening to another type of cardiovascular screening. A dynamic random effects bivariate panel probit model with initial conditions (Wooldridge-type estimator) was adopted for the estimation. The outcome variables were the participation in blood pressure and cholesterol level checks by individuals in a given year. The balanced panel sample of 21,138 observations was constructed from 1,626 individuals from the British Household Panel Survey (BHPS) between 1996 and 2008. The analysis showed the significance of past screening behaviour for both cardiovascular screening examinations. For both cardiovascular screening examinations state dependence exist. The study also shows a significant spillover effect of the cholesterol level check on the blood pressure check and vice versa. Also a poorer health status led to a higher uptake for both types of screening examinations. Changes in recommendations have to consider the fact that taking part in one type of cardiovascular screening examination can influence the decision to take part in the other type of cardiovascular screening examination.